Genotypes at the APOE and SCA2 loci do not predict the course of multiple sclerosis in patients of Portuguese origin

Prova tipográfica (In Press)Multiple sclerosis (MS) is a demyelinating disease that affects about one in 500 young Europeans. In order to test the previously proposed influence of the APOE and SCA2 loci on susceptibility to MS, we studied these loci in 243 Portuguese patients and 192 healthy controls and both parents of 92 patients. We did not detect any significant difference when APOE and SCA2 allele frequencies of cases and controls were compared, or when we compared cases with different forms of the disease. Disequilibrium of transmission was tested for both loci in the 92 trios, and we did not observe segregation distortion. To test the influence of the APOE o4 and SCA2 22 CAGs alleles on severity of disease, we compared age at onset and progression rate between groups with and without those alleles. We did not observe an association of the o4 or the 22 CAGs alleles with rate of progression in our total patient population; allele o4 was associated with increased rate of progression of MS in a subset of patients with less than 10 years of the disease. However, globally in the Portuguese population, the APOE and SCA2 genes do not seem to be useful in the clinical context as prognostic markers of this disorder.Fundação para a Ciência e a Tecnologia (FCT) - grant SFRH/BD/9111/2002.Serono Portugal

Learning from the UK’s research impact assessment exercise: a case study of a retrospective impact assessment exercise and questions for the future

National governments spend significant amounts of money supporting public research. However, in an era where the international economic climate has led to budget cuts, policymakers increasingly are looking to justify the returns from public investments, including in science and innovation. The so-called ‘impact agenda’ which has emerged in many countries around the world is part of this response; an attempt to understand and articulate for the public what benefits arise from the research that is funded. The United Kingdom is the most progressed in implementing this agenda and in 2014 the national research assessment exercise, the Research Excellence Framework, for the first time included the assessment of research impact as a component. For the first time within a dual funding system, funding would be awarded not only on the basis of the academic quality of research, but also on the wider impacts of that research. In this paper we outline the context and approach taken by the UK government, along with some of the core challenges that exist in implementing such an exercise. We then synthesise, together for the first time, the results of the only two national evaluations of the exercise and offer reflections for future exercises both in the UK and internationally

Peroxiredoxin 6 in human brain: molecular forms, cellular distribution and association with Alzheimer’s disease pathology

Peroxiredoxin 6 is an antioxidant enzyme and is the 1-cys member of the peroxiredoxin family. Using two-dimensional electrophoresis and Western blotting, we have shown for the first time that, in human control and brain tissue of patient’s with Alzheimer’s disease (AD), this enzyme exists as three major and five minor forms with pIs from 5.3 to 6.1. Using specific cellular markers, we have shown that peroxiredoxin 6 is present in astrocytes with very low levels in neurons, but not detectable in microglia or oligodendrocytes. In control brains, there was a very low level of peroxiredoxin 6 staining in astrocytes that was confined to a “halo” around the nucleus. In AD, there were marked increases in the number and staining intensity of peroxiredoxin 6 positive astrocytes in both gray and white matter in the midfrontal cortex, cingulate, hippocampus and amygdala. Confocal microscopy using antibodies to Aβ peptide, tau and peroxiredoxin 6 showed that peroxiredoxin 6 positive astrocytes are closely involved with diffuse plaques and to a lesser extent with neuritic plaques, suggesting that plaques are producing reactive oxygen species. There appeared to be little astrocytic response to tau containing neurons. Although peroxiredoxin 6 positive astrocytes were seen to make multiple contacts with tau positive neurons, there was no intraneuronal colocalization. In brain tissue of patients with AD, many blood vessels exhibited peroxiredoxin 6 staining that appeared to be due to the astrocytic foot processes. These results suggest that oxidative stress conditions exist in AD and that peroxiredoxin 6 is an important antioxidant enzyme in human brain defenses

Polymorphisms of the cannabinoid 1 receptor gene and cognitive impairment in multiple sclerosis

“The final, definitive version of this article has been published in the Journal, Multiple Sclerosis, 14 (2) 2008, © SAGE Publications Ltd, 2008: on SAGE Journals Online: http://online.sagepub.com/” [Full text of this article is not available in the UHRA]Cognitive impairment occurs in 45—65% of multiple sclerosis (MS) patients. The cannabinoid system may potentially be neuroprotective in MS. We examined the relationship between polymorphisms of the CNR1 gene and neuropsychological outcome in MS using a test and confirmatory sample of patients. One hundred and ninety-four MS patients were assessed over five key areas of neuropsychological function, which are most commonly impaired in MS. The first 97 patients formed the test sample. A further confirmatory sample of 97 patients was used to test association found in the test sample. The schedule included: Wisconsin card sorting test 64 version, Rey auditory verbal learning task immediate and delayed scores, controlled oral word association task, judgement of line orientation and symbol digit modalities task. Three single nucleotide polymorphisms (SNPs) were typed within the CNR1 gene. For the overall neuropsychological assessment score we used a multiple linear regression model with selected covariates to show that subjects with the AA genotype of the SNP RS1049353 were more impaired (mean -2.47, SD 5.75, P = 0.008, Bonferroni corrected P = 0.024) than the other subjects (mean 0.24, SD 4.24). This was not confirmed when the association was retested in the confirmatory sample. No associations were identified between these CNR1 variants and cognitive impairment in MS.Peer reviewe